title: Pharmacokinetics and safety of the co-administration of the antiretroviral raltegravir and the lipid-lowering drug ezetimibe in healthy volunteers.
abstract: OBJECTIVE
  To assess the pharmacokinetics (PK) of raltegravir and ezetimibe when co-administered to healthy volunteers.
  
  
  METHODS
  This was a prospective, open-label, crossover study, with subjects randomly assigned to group 1 (raltegravir 400 mg twice daily, raltegravir plus ezetimibe 10 mg once daily, wash-out period, ezetimibe) or group 2 (ezetimibe, raltegravir plus ezetimibe, wash-out period, raltegravir); all phases lasted for 10 days. Steady-state full PK sampling was performed at days 10, 20 and 40. Raltegravir and ezetimibe PK parameters were determined by non-compartmental methods and comparisons in the presence of the potentially interactive drug measured by geometric mean ratio (GMR) and 95% confidence intervals (CIs).
  
  
  RESULTS
  Twenty subjects (10 females) completed the study. Raltegravir PK parameters did not change significantly in the presence of ezetimibe: GMRs (95% CI) were 1.16 (0.89-1.51) for AUC(0-12), 1.13 (0.81-1.58) for maximum plasma concentration (Cmax) and 1.12 (0.72-1.74) for trough concentration (Ctrough). Ezetimibe AUC0-24 and Ctrough were lower in the presence of raltegravir [GMRs (95% CI) were 0.79 (0.68-0.91) for AUC0-24 and 0.78 (0.60-0.99) for Ctrough], while ezetimibe glucuronide Cmax was 40% higher (90% CI 1.17-1.66). There was marked inter-individual variability in the PK of the two drugs, especially during co-administration.
  
  
  CONCLUSIONS
  There were no significant changes in raltegravir PK parameters with or without ezetimibe. However, in the presence of raltegravir, ezetimibe AUC0-24 and Ctrough were significantly lower (>20%) and ezetimibe glucuronide Cmax was higher. Clinical data to assess the importance of the change in ezetimibe concentrations are warranted.
authors.affiliation: St Stephen's Centre, Chelsea and Westminster Hospital, London, UK.
authors.forename: Akil
authors.initials: A
authors.lastname: Jackson
authors.forename: Antonio
authors.initials: A
authors.lastname: D'Avolio
authors.forename: Victoria
authors.initials: V
authors.lastname: Watson
authors.forename: Stefano
authors.initials: S
authors.lastname: Bonora
authors.forename: David
authors.initials: D
authors.lastname: Back
authors.forename: Jessica
authors.initials: J
authors.lastname: Taylor
authors.forename: Kostantinos
authors.initials: K
authors.lastname: Armenis
authors.forename: Brian
authors.initials: B
authors.lastname: Gazzard
authors.forename: Graeme
authors.initials: G
authors.lastname: Moyle
authors.forename: Marta
authors.initials: M
authors.lastname: Boffito
mesh_terms: D000328:Adult; D000924:Anticholesteremic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D000998:Antiviral Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D001384:Azetidines / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D018592:Cross-Over Studies; D004359:Drug Therapy, Combination / Q000009:adverse effects / Q000379:methods; D000069438:Ezetimibe; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D011760:Pyrrolidinones / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D000068898:Raltegravir Potassium
chemical_list: D000924:Anticholesteremic Agents; D000998:Antiviral Agents; D001384:Azetidines; D011760:Pyrrolidinones; D000068898:Raltegravir Potassium; D000069438:Ezetimibe